Evaluating the heritability of glaucoma

In the Ocular Hypertension Treatment Study (OHTS), a self-reported family history of glaucoma was not linked to the development of glaucoma. Noting that in an introduction to his own recent glaucoma study, John Landers, M.B.B.S., M.P.H., Department of Ophthalmology, Flinders Medical Centre, Bedford Park, Australia, still wasn’t convinced OHTS had it completely right. He set out to investigate whether variations in central corneal thickness—which have been associated with glaucoma—could be heritable in nuclear families.
“Because patients with ocular hypertension have significantly increased CCT [central corneal thickness], we speculated that if CCT shows high heritability in nuclear families, then perhaps some cases of self-reported family history of glaucoma in the OHTS were actually family members with ocular hypertension and thick CCT receiving treatment,” Dr. Landers reported online in May in Investigative Ophthalmology & Visual Science. “A familial pattern of CCT might therefore have led to a lack of association between having a self-reported family history of glaucoma and the development of glaucoma.”

Delving deeper

First, Dr. Landers and colleges found 33 index cases—people with a known CCT that deviated widely from the CCT people have on average. The typical CCT was considered to be 544 microns, based on a previously published meta-analysis mean.
Thick index cases were therefore considered to be greater than 578 microns (representing +/–1 standard deviation from that previously published mean) and thin cases were less than 510 microns (also +/–1 standard deviation).
CCT was then measured in all available family members of the index cases, which included 55 offspring and 10 siblings.
CCT of children of the nuclear family thick index cases was 568 microns, while CCT of children of the thin index cases was 521 microns. This difference was statistically significant.
“When the correlation between index parent CCT and the mid-child CCT was examined, it yielded a parent-child heritability estimate for CCT of h2=0.68,” Dr. Landers reported. “The excellent correlation between heritability estimates by two different methods provides additional confidence in the results.”
Siblings of thick CCT index cases also had a mean CCT of 590 microns, and siblings of thin CCT index cases had a mean CCT of 507 microns. Apparently, brothers of thick cornea brothers often have thick corneas themselves, and the same goes for sisters.
Heritability of thin CCT also becomes more likely if both parents have thin CCT, the study found.
“Among family units with one parent who had a thin CCT, 28% (8/29) of offspring demonstrated a thin CCT,” Dr. Landers reported. “However, if a family unit had two parents with a thin CCT, then 72% (8/11) of offspring were similarly thin. Among family units with one parent who had a thin CCT, 28% (8/29) of offspring demonstrated a thin CCT. However, if a family unit had two parents with a thin CCT, then 72% (8/11) of offspring were similarly thin.”
The results, therefore, suggest CCT is heritable, and they also allude to some other insights, according to Dr. Landers:
It is reasonable to try to map genes for CCT in the future.
The environment likely has little effect on CCT. “As CCT changes very little throughout adult life and our data suggests no significant difference between spouses of thin or thick index cases, there does not seem to be a major effect of environment on this trait,” Dr. Landers noted.
People with a thick CCT and ocular hypertension without glaucoma likely have close relatives in a similar situation. First-degree relatives might be on glaucoma drops even though they lack other hallmark signs of glaucoma and have a low risk of developing glaucoma despite their higher IOPs.
On the other hand, thin CCT has been linked to glaucoma. “An understanding of CCT heritability could flag first-degree relatives of those with severe glaucoma and thin CCT as individuals for clinical assessment and more careful surveillance,” Dr. Landers noted.
It makes sense that corneal thickness could be genetically influenced, said Francis S. Mah, M.D., co-medical director, Charles T. Campbell Ophthalmic Microbiology Laboratory, University of Pittsburgh School of Medicine, Pittsburgh.
“Genetically, corneas may be similar,” Dr. Mah said. “Other conditions that are transmitted by classic genetics include many stromal dystrophies, so it makes sense that corneal thickness in general could be passed down from parent to offspring.”
However, other corneal thinning disorders such as keratoconus, pellucid marginal degeneration, and keratoglobus are not associated with classic Mendelian genetic laws, Dr. Mah noted, although genetic transmission could still play some role.
Dr. Landers suggested further detailed understanding of how exactly CCT is inherited should be forthcoming in future research.
“Further understanding of modes of inheritance and segregation will follow once the genes determining CCT variation in normal individuals are identified,” Dr. Landers reported.

Editors’ note: Dr. Landers has no financial interests related to this study. Dr. Mah has no financial interests related to his comments.

Contact information

Landers: john.landers@bigpond.com
Mah: 412-647-2211, mahfs@upmc.edu